Project summary: This project is designed to evaluate a new class of anti-cancer agents for treatment of invasive melanoma, pancreas, lung, and colon carcinomas. The study compounds are small, synthetic molecules that have not previously been used in people, and bind to a surface receptor on tumor cells that has not previously been targeted in cancer. Strong preliminary results indicate that the study compounds potentiate the efficacy of the new immune checkpoint inhibitors that are now the standard of care for metastatic melanoma. In this proposal, we will determine dosing regimens that will maximize the anti-cancer effects, define biomarkers that correlate with tumor response, and determine whether the anti-melanoma synergy between G-1 and ?PD-1 extends to other immune checkpoint inhibitors. Completion of the proposed work will contribute to the completion of IND-enabling work necessary to translate these discoveries to first in human trials.